Modeling of cell-specific LRP1 signaling in acute myocardial infarction

SUMMARY Modeling cell-specific LRP1 signaling in acute myocardial infarction Improving the treatment of acute myocardial infarction (AMI) to prevent heart failure (HF) and death remains an urgent unmet medical need. The AHA estimates that every 42 seconds an American will have an AMI, and despite the improvement in treatment and prognosis, a significant number of patients develop continue to

develop HF or die. The AHA estimates that 17-years of life are lost due to AMI. With a rising prevalence and high incidence (>900,000 new cases per year in USA alone), AMI and HF are important public enemies. Low-density lipoprotein receptor related protein-1 (LRP1) is a membrane receptor known as scavenger for the

serine protease inhibitor (SERPIN)-enzyme complex (SEC), linked to anti-inflammatory and cytoprotective signaling. We and others have described the protective activities of LRP1 in ischemia-reperfusion injury during AMI. We showed that non-selective LRP1 agonists, and more recently, that a targeted small peptide selectively

engaging LRP1, SP16, reduced infarct size in experimental animal models. LRP1's role in ischemia-reperfusion injury and infarct healing is, however, complex as LRP1 is involved not only in the cell survival pathway but also in the wound healing and repair process regulating fibroblast proliferation.

We hypothesize that after acute myocardial infarction, LRP1 transduces an early beneficial cardiomyocyte-specific signaling network but a late detrimental fibroblast-specific signaling network that can be leveraged for therapeutic purposes. We will test this overall hypothesis by combining cell-specific

network modeling with cellular and mouse experiments in two specific aims. In Aim #1, we expand and experimentally validate a signaling network that predicts how early cardiomyocyte LRP1 signaling enhances cell survival after ischemia-reperfusion in cells and mice. Network modeling combining LRP1 mechanisms, survival signaling, and downstream ischemia-reperfusion modules will predict network

mechanisms mediating LRP1-dependent survival. Experiments will leverage pharmacologic and our new cardiomyocyte-specific LRP1 gene KO mouse model with subject to AMI. In Aim #2, we will expand and experimentally validate a signaling network that predicts how late fibroblast LRP1 signaling stimulates fibrotic

phenotypes in cells and mice. We will integrate single-cell RNA-sequencing with fibroblast network modeling that identifies LRP1-dependent pathways in AMI. These will be validated using our new fibroblast-specific LRP1 gene KO mouse model subject to AMI. Together, computational-experimental studies of cell-specific LRP1 signaling

networks will reveal how early exogenous LRP1 agonists promote cardiomyocyte survival while late endogenous LRP1 agonists promote fibrosis. These insights will provide distinct therapeutic targeting opportunities for AMI and HF.